US5660859A - Gelling agent for polyethylene glycol - Google Patents

Gelling agent for polyethylene glycol Download PDF

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Publication number
US5660859A
US5660859A US08/366,271 US36627194A US5660859A US 5660859 A US5660859 A US 5660859A US 36627194 A US36627194 A US 36627194A US 5660859 A US5660859 A US 5660859A
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US
United States
Prior art keywords
gel
polyethylene glycol
calcium acetate
percent
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US08/366,271
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English (en)
Inventor
Sharon L. Cody
Michael R. Hoy
Eric J. Walter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johnson and Johnson Consumer Inc
Original Assignee
McNeil PPC Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by McNeil PPC Inc filed Critical McNeil PPC Inc
Priority to US08/366,271 priority Critical patent/US5660859A/en
Assigned to MCNEIL-PPC, INC. reassignment MCNEIL-PPC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CODY, SHARON L., HOY, MICHAEL R., WALTER, ERIC J.
Priority to NZ280609A priority patent/NZ280609A/en
Priority to AU40502/95A priority patent/AU692959B2/en
Priority to JP7351256A priority patent/JPH08253412A/ja
Priority to DE69509055T priority patent/DE69509055T2/de
Priority to DK95309508T priority patent/DK0719548T3/da
Priority to EP95309508A priority patent/EP0719548B1/de
Priority to ZA9511033A priority patent/ZA9511033B/xx
Priority to ES95309508T priority patent/ES2131776T3/es
Priority to US08/874,257 priority patent/US5840337A/en
Publication of US5660859A publication Critical patent/US5660859A/en
Application granted granted Critical
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/14Antitussive agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to gelling liquid polyethylene glycol at room temperature to produce a substantially translucent gel suitable for use in pharmaceutical or cosmetic products.
  • soft gelatin or soft elastic gelatin capsules have become a popular dosage form for the oral delivery of therapeutic agents, especially over-the-counter pharmaceuticals. These capsules are typically filled with a liquid containing the active ingredient. Because of their soft, elastic character, some patients view these capsules as easier to swallow than conventional tablets or hard gelatin capsules. Since the dosage form is generally swallowed, it is not necessary to flavor or otherwise mask the often unpleasant taste of the pharmaceutical. Soft gelatin capsules are also preferred to bulk liquids because they are easier to transport and they avoid the need for the patient to measure a prescribed amount of the liquid before dosing.
  • the fill material used in a soft gelatin capsules generally contains a pharmaceutical dissolved or dispersed in a carrier that is compatible with the capsule wall.
  • a carrier that is compatible with the capsule wall.
  • U.S. Pat. No. 4,935,243 to L. Borkan et al. suggests that the fill material may take the form of a semi-solid, solid, or gel.
  • Conventional tablets or pellets containing an active ingredient are examples of solid fill materials that may be encapsulated within a soft gelatin capsule.
  • the carrier forms a stable dispersion of the antacid salt and coats the antacid particles, thereby rendering them non-reactive with the soft gelatin capsule wall.
  • U.S. Pat. No. 4,708,834 to Cohen et al. suggests a controlled release pharmaceutical dosage form comprising a soft gelatin capsule that encloses a water-soluble or dispersible gelled polymer matrix.
  • the fill material comprises an aqueous solution or dispersion of a polysaccharide gum, the pharmaceutical active and, optionally, an alcohol.
  • the liquid fill is introduced into a soft gelatin capsule that contains a cationic gelling agent, which gels the liquid fill after it has been incorporated into the capsule shell.
  • the alcohol used in the fill includes liquid polyethylene glycols, lower alkanols, C 2 -C 4 polyols and mixtures thereof.
  • PEG polyethylene glycols
  • PCT Publication No. WO 91/07950 describes a soft or two-piece hard gelatin capsule shell containing benzodiazepine dissolved or suspended in a gel.
  • the gel contains by weight at least 63% of polyethylene glycol 600, at least 4% of polyethylene glycol 4000 or 6000, and at least 21% of polyethylene glycol 600-4000. This gel fill cannot be expelled with a syringe at ambient temperature and therefore avoids the reported abuse of liquid filled capsules by intravenous drug abusers.
  • gelling agents used to make gels for pharmaceutical and cosmetic products include sodium alginate and triethanolamine.
  • the present invention provides a technique for gelling liquid polyethylene glycols at room temperature.
  • the gel is suitable for use as a fill material in a soft gelatin capsule pharmaceutical dosage form, a carrier for a pharmaceutical in a topical formulation, or as a base for a cosmetic or dental care product.
  • the gel comprises a liquid polyethylene glycol, water and an effective amount of calcium acetate to gel the glycol.
  • the gel of the present invention has a substantially translucent appearance, and when used to fill a soft gelatin capsule or as base in a cosmetic care product, the resulting product has an elegant, substantially translucent appearance.
  • the present invention provides a technique for gelling liquid polyethylene glycols at room temperature.
  • the resulting gel is substantially translucent and may be used as a carrier for a pharmaceutical in a soft gelatin capsule, topical formulation or two-piece hard gelatin capsule.
  • the present invention provides a number of processing advantages. No heating or cooling is required, so the manufacture process is simple and inexpensive. The resulting gel also has relatively few components, which helps to reduce the number of mixing steps in the process.
  • the liquid polyethylene glycol has an average molecular weight of about 600 or less, preferably about 200 to about 600, and most preferably about 300 to about 400. A minor proportion of water is also used in conjunction with the polyethylene glycol.
  • the gel generally comprises by weight about 40 to about 80, preferably about 50 to about 70, percent polyethylene glycol and about 1 to about 40, preferably about 5 to about 25, percent water. Unless otherwise stated, the percentages recited herein are by weight of the total weight of the gel fill material, i.e., both the gel and active ingredient.
  • the calcium acetate is employed in an amount effective to form a gel at room temperature that has the desired viscosity or gel strength. Generally the gel contains by weight from about 0.5 to about 10, preferably about 0.5 to about 5 percent calcium acetate.
  • the calcium acetate may me used in either an anhydrous or hydrated form.
  • the viscosity or gel strength is dependent upon the end use of the gel.
  • the gel should be sufficiently viscous so that it cannot be expelled at room temperature with a syringe. This feature helps to protect against possible intravenous abuse of the drug as well as product tampering.
  • topical pharmaceutical and/or cosmetic applications such as for use as a spreadable gel, ointment or lotion, the gel need not be as viscous.
  • the viscosity or gel strength is also affected by an increase or decrease in the amount of shear applied in the manufacturing process. It was found that the amount of shear and the length of mixing have an effect on the strength of the gel. A large amount of shear decreases the strength of the gel and, likewise, a minimal amount of shear increases the strength of the gel. Also, it was found that the best way to maximize the strength of the gel is by decreasing shear and, most preferably, by eliminating any mixing. Therefore, a dual head filling process directly into the soft gelatin capsule without any mixing is the best means for achieving a strong gel fill material suitable for soft gelatin capsule applications. A manufacturing process with sufficient mixing is the best means for achieving a low viscosity gel material suitable for topical applications.
  • Solubilizing agents may also be employed to enhance the solubility or dispersibility of the active ingredient in the gel.
  • Suitable agents include:
  • the pharmaceutical active used in the present invention can be any medication which can be administered orally to transmit the active agent into the gastrointestinal tract and into the bloodstream at therapeutically effective levels.
  • the pharmaceutical active(s) is present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration, and can be readily determined by one skilled in the art. In determining such amounts, the particular compound being administered, the bio-availability characteristics of the compound, the dose regiment, the age and weight of the patient, and other factors must be considered.
  • Pharmaceuticals suitable for use in the invention include acetaminophen, famotidine, chlorpheniramine, pseudoephedrine, dextromethorphan, diphenhydramine, brompheniramine, phenylpropanolamine, clemastine, terfenadine, astemizole, loratadine, pharmaceutically acceptable salts thereof and mixtures thereof.
  • compositions may be included in the pharmaceutical dosage form, such as preservatives, e.g., methyl- or propylparaben, and coloring agents.
  • a fill for a soft gelatin capsule containing about 250 mg/ml of acetaminophen comprises by weight from about 23 to about 27 percent acetaminophen, from about 60 to about 70 percent PEG 400, from about 10 to about 20 percent water, and from about 1 to about 3 percent calcium acetate.
  • Suitable active ingredients for use in topical pharmaceutical formulations include antifungals, anti-inflammatory corticosteroids, antibiotics, otic-active ingredients, ophthalmic-active ingredients, anti-acne medicaments, and nasal-active ingredients.
  • Suitable active ingredients for use in cosmetic and dental care products include deodorants, sodium fluoride, anti-perspirants, perfumes, and skin moisturizers.
  • the amount of the active ingredient, whether a pharmaceutical or an active in a cosmetic, employed in the gel will vary depending on the potency of the active and the desired strength of the dosage form or product. Generally, the active ingredient comprises about 0.1 to about 40, preferably about 0.2 to about 30, percent by weight of the total gel composition.
  • the active ingredient, at the desired dosage must also be sufficiently soluble or dispersible in the gel so that the resulting composition has a turbidity of less than about 1300 NTU (Nephelometric Turbidity Unit).
  • the gel is prepared by first forming an aqueous calcium acetate solution.
  • the active ingredient(s) is then mixed with the liquid polyethylene glycol and the solubizing agent, if any, being used in the formulation.
  • the aqueous calcium acetate solution is combined with the actives mixture at room temperature. It can be mixed gently for lower viscosity gels (spreadable). For higher viscosity gels (semi-solid like), the calcium acetate solution and the actives mixture are combined in a dual head filling mechanism without any additional mixing. The mixture resulting from the dual head filling device is then left undisturbed for about 5 to about 60 minutes to effect gelling.
  • the fill material of the present invention may be used in commercially available soft gelatin capsules, such as those commercially available from R. P. Scherer or Banner Pharmacaps. Various sizes, shapes, and colors can be used to accommodate different levels of active ingredients.
  • the walls of the capsules have a substantially translucent or clear appearance. When the fill material of the present invention is introduced into the capsule and gelled, the resulting dosage form has an elegant, translucent or clear appearance.
  • the gel is formed at ambient room temperature in the capsule after the two component mixture, namely the PEG/actives mixture and the calcium acetate solution, are injected separately.
  • the needle on the syringe is used to puncture one end of the soft gelatin capsule so that the appropriate amount of the two component mixtures may be injected by hand.
  • the capsule with fill material is allowed to set undisturbed at ambient room temperature to effect gelling.
  • the fill material may also be introduced into the soft gelatin capsule using encapsulation equipment known in the art, such as that described in U.S. Pat. No. 4,028,024 to Moreland, which is hereby incorporated by reference. Such equipment, however, requires the use of a dual head to introduce the two component mixtures into the gelatin shell as separate streams.
  • the turbidity of the fill materials described in the following examples was measured using a Hach Ratio/XR Turbidimeter.
  • the United States Pharmacopedia defines turbidance as the light-scattering effect of suspended particles and turbidity as the measure of the decrease in the incident beam intensity per unit length of a given suspension. This instrument measures turbidity within a range of 0.00 to 2000 NTU. As a point of reference, the turbidity of water is zero.
  • Samples of the fill materials approximately 8 mL, were transferred to Fisher Brand 13 ⁇ 100 mm culture tubes immediately after manufacture. The fill material samples were stored at ambient room temperature since they were made several days in advance. The outer surface of each of the sample culture tubes was treated with silicone oil just prior to measuring the turbidity. The turbidity of the samples was measured at ambient room temperature. The turbidity of two sample tubes of each fill material was measured and the average of the results is reported.
  • This Example reports the results of an experiment wherein different salts were evaluated as potential gelling agents for liquid polyethylene glycol at room temperature.
  • composition shown below was prepared at room temperature by solubilizing the salt in water and then mixing with PEG 400 to see if a gel would form at ambient room temperature.
  • This Example discloses a composition of the present invention which was gelled at room temperature with calcium acetate.
  • the gel contained:
  • the sample was prepared as follows:
  • the resulting gel had a translucent appearance.
  • This Example discloses a acetaminophen-containing composition of the present invention which was gelled at room temperature with calcium acetate.
  • the gel contained:
  • the sample was prepared as follows:
  • step 3 One part of the solution of step 1) was mixed with nine parts of the mixture of step 2). The resulting mixture was allowed to gel at room temperature.
  • the resulting gel had a translucent appearance.
  • This Example discloses a composition of the present invention which was gelled at room temperature with calcium acetate.
  • the gel contained:
  • the gel was prepared as follows:
  • the fill material was substantially clear and had a turbidity of 195 NTU, although some air was noted in the tested samples.
  • This Example discloses a fill material of the present invention containing 200 mg/mL of acetaminophen which was gelled at room temperature with calcium acetate.
  • the fill material contained:
  • the samples was prepared as follows:
  • the fill material was substantially translucent and had a turbidity of 865 NTU, although some air was noted in the tested samples.
  • the resulting fill material could be expelled at room temperature with a syringe having an 18 gauge needle because the strength of the gel was weakened by the mixing step. It was found that the gel strength can be maximized by eliminating the mixing step.
  • the sample was prepared a second time by first hand-filling a soft gelatin capsule shell with the active/PEG slurry with a syringe. Then the calcium acetate solution was injected into the capsule shell containing the active/PEG slurry. The resulting mixture was allowed to gel at room temperature in the capsule shell. The capsule was then cut open with a scalpel and the fill material was observed to be a solid material.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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US08/366,271 1994-12-29 1994-12-29 Gelling agent for polyethylene glycol Expired - Lifetime US5660859A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US08/366,271 US5660859A (en) 1994-12-29 1994-12-29 Gelling agent for polyethylene glycol
NZ280609A NZ280609A (en) 1994-12-29 1995-12-06 Gelling liquid polyethylene glycol compostions which includes water and calcium acetate, and its use in medicaments, cosmetics and dental care
AU40502/95A AU692959B2 (en) 1994-12-29 1995-12-18 Gelling agent for polyethylene glycol
JP7351256A JPH08253412A (ja) 1994-12-29 1995-12-27 ポリエチレングリコールのためのゲル化剤
EP95309508A EP0719548B1 (de) 1994-12-29 1995-12-28 Gelierungsmittel für polyethylene Glycol
DK95309508T DK0719548T3 (da) 1994-12-29 1995-12-28 Geleringsmiddel for polyethylenglycol
DE69509055T DE69509055T2 (de) 1994-12-29 1995-12-28 Gelierungsmittel für polyethylene Glycol
ZA9511033A ZA9511033B (en) 1994-12-29 1995-12-28 Gelling agent for polyethylene glycol
ES95309508T ES2131776T3 (es) 1994-12-29 1995-12-28 Agente gelificante para el polietilenglicol.
US08/874,257 US5840337A (en) 1994-12-29 1997-06-13 Gelling agent for polyethylene gylcol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/366,271 US5660859A (en) 1994-12-29 1994-12-29 Gelling agent for polyethylene glycol

Related Child Applications (1)

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US08/874,257 Division US5840337A (en) 1994-12-29 1997-06-13 Gelling agent for polyethylene gylcol

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US5660859A true US5660859A (en) 1997-08-26

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US08/366,271 Expired - Lifetime US5660859A (en) 1994-12-29 1994-12-29 Gelling agent for polyethylene glycol
US08/874,257 Expired - Lifetime US5840337A (en) 1994-12-29 1997-06-13 Gelling agent for polyethylene gylcol

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US08/874,257 Expired - Lifetime US5840337A (en) 1994-12-29 1997-06-13 Gelling agent for polyethylene gylcol

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US (2) US5660859A (de)
EP (1) EP0719548B1 (de)
JP (1) JPH08253412A (de)
AU (1) AU692959B2 (de)
DE (1) DE69509055T2 (de)
DK (1) DK0719548T3 (de)
ES (1) ES2131776T3 (de)
NZ (1) NZ280609A (de)
ZA (1) ZA9511033B (de)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840337A (en) * 1994-12-29 1998-11-24 Mcneil-Ppc, Inc. Gelling agent for polyethylene gylcol
US6245795B1 (en) 1997-03-31 2001-06-12 Kanebo, Limited Melanogenesis inhibitor, skin cosmetic composition and bath preparation
US6251426B1 (en) 1999-09-02 2001-06-26 Banner Pharmacaps, Inc. Ibuprofen-containing softgels
US6322811B1 (en) 1998-02-06 2001-11-27 Union Carbide Chemicals & Plastics Technology Corporation Alkylene oxide polymer compositions
US6391282B1 (en) * 1997-11-10 2002-05-21 Flemington Pharmaceutical Corp. Antihistamine sprays and ointments for relief of delayed contact dermatitis
US20040037766A1 (en) * 2002-08-21 2004-02-26 Akpharma, Inc. Compositions and methods for treating skin conditions
US20080107743A1 (en) * 2006-11-02 2008-05-08 Akpharma Inc. Composition and method for enhancing skin cell growth, proliferation and repair
US20100255070A1 (en) * 2007-05-22 2010-10-07 Prelief Inc. Compositions and methods for preventing, minimizing and healing skin irritation and trauma

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AU2003200609B2 (en) * 1998-05-18 2006-02-23 Amgen Inc. Biodegradable sustained-release alginate gels
US6432449B1 (en) * 1998-05-18 2002-08-13 Amgen Inc. Biodegradable sustained-release alginate gels
WO2002036077A2 (en) * 2000-11-06 2002-05-10 Andrx Pharmaceuticals, Inc. Once a day antihistamine and decongestant formulation
US20030060422A1 (en) 2001-08-31 2003-03-27 Balaji Venkataraman Tannate compositions and methods of treatment
US8092831B2 (en) * 2002-11-08 2012-01-10 Andrx Pharmaceuticals, Llc Antihistamine and decongestant system
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
CA2775890C (en) * 2009-09-30 2016-06-21 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
MX366159B (es) 2012-11-30 2019-07-01 Acura Pharmaceuticals Inc Liberacion autorregulada de ingrediente farmaceutico activo.
WO2015023675A2 (en) 2013-08-12 2015-02-19 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
AU2015237723B2 (en) 2014-03-26 2018-04-26 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release biphasic matrix solid dosage form
CA2955229C (en) 2014-07-17 2020-03-10 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
JP2017531026A (ja) 2014-10-20 2017-10-19 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド 徐放性乱用抑止性液体充填剤形
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
CN109276549B (zh) * 2018-11-21 2020-07-21 海南赛立克药业有限公司 醋酸钙片及其制备方法

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EP0719548B1 (de) 1999-04-14
DE69509055D1 (de) 1999-05-20
AU4050295A (en) 1996-07-04
DE69509055T2 (de) 1999-08-19
DK0719548T3 (da) 1999-06-23
US5840337A (en) 1998-11-24
ZA9511033B (en) 1997-06-30
EP0719548A1 (de) 1996-07-03
AU692959B2 (en) 1998-06-18
NZ280609A (en) 1997-11-24

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